Document:

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                                                                     EXHIBIT 4.9

                                                                  EXECUTION COPY
                                                                  --------------

                                AMENDMENT NO. 1
                                       TO
                         REGISTRATION RIGHTS AGREEMENT

     AMENDMENT NO. 1, dated as of February 27, 1996 by and among Adolor
Corporation, a Delaware corporation (the "Company"), certain holders of the
Company's outstanding securities (collectively, the "Existing Investors") and
those purchasers listed in Schedule I to the Series B Convertible Preferred
Stock Purchase Agreement (the "Purchase Agreement") dated the date hereof
(collectively, including such purchasers who participate in any Additional
Closing (as defined in the Purchase Agreement) and who execute a counterpart to
this Agreement, the "Purchasers").

     WHEREAS, the Company and the Existing Investors are parties to that
Registration Rights Agreement (the "Registration Rights Agreement") by and among
the Company and the parties named therein dated as of the 7th day of November
1994; and

     WHEREAS, the Purchasers are purchasing from the Company and the Company is
issuing and selling to the Purchasers up to 19,964,286 shares (the "Series B
Shares") of Series B Convertible Preferred Stock, par value $.01, ("Series B
Stock") of the Company at the aggregate purchase price of up to $8,385,000
pursuant to the Purchase Agreement, and

     WHEREAS, it is a condition to the sale of the Series B Stock that the
Registration Rights Agreement be amended to grant the Purchasers certain rights
thereunder, and the parties hereto desire to amend the Registration Rights
Agreement as set forth below;

     NOW, THEREFORE in consideration of the foregoing and the promises and
covenants contained herein, the parties hereby agree as follows:

1.   That Section 1 be and hereby is amended to add the following definition in
     appropriate alphabetical order:

         "Preferred Shares" shall mean shares of the Company's Series A
         Convertible Preferred Stock, par value $.01 and Series B Convertible
         Preferred Stock, par value $.01.

2.   Capitalized terms used but not otherwise defined herein shall have the
     meanings ascribed to them in the Registration Rights Agreement.

3.   In all other respects, the Registration Rights Agreement is hereby
     ratified, confirmed and approved, and all terms thereof shall remain in
     fill force and effect.
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4.   This Amendment No. 1 may be executed in counterparts, each of which shall
     constitute an original, but all of which, when taken together, shall
     constitute but one agreement.

                      [Signature Pages Follow Immediately]

                                      -2-<PAGE>

                                                                    EXHIBIT 4.10

                                AMENDMENT NO. 2
                                       TO
                         REGISTRATION RIGHTS AGREEMENT

     AMENDMENT NO. 2, dated as of May 1, 1997 by and among Adolor Corporation, a
Delaware corporation (the "Company"), certain holders of the Company's
outstanding securities (collectively, the "Existing Investors") and those
purchasers listed in Schedule I to the Series C Convertible Preferred Stock
Purchase Agreement (the "Purchase Agreement") dated the date hereof
(collectively, including such purchasers who participate in any Additional
Closing (as defined in the Purchase Agreement) and who execute a counterpart to
this Agreement, the "Purchasers").

     WHEREAS, the Company and the Existing Investors are parties to that
Registration Rights Agreement (the "Registration Rights Agreement") by and among
the Company and the parties named therein dated as of the 7th day of November
1994, as amended by Amendment No. 1 to Registration Rights Agreement dated as of
February 27, 1996; and

     WHEREAS, the Purchasers are purchasing from the Company and the Company is
issuing and selling to the Purchasers up to 14,285,714 shares (the "Series C
Shares") of Series C Convertible Preferred Stock, par value $.01, ("Series C
Stock") of the Company at the aggregate purchase price of up to $10,000,000
pursuant to the Purchase Agreement, and

     WHEREAS, it is a condition to the sale of the Series C Shares that the
Registration Rights Agreement be amended to grant the Purchasers certain rights
thereunder, and the parties hereto desire to amend the Registration Rights
Agreement as set forth below;

     NOW, THEREFORE in consideration of the foregoing and the promises and
covenants contained herein, the parties hereby agree as follows:

1.   That Section 1 of the Registration Rights Agreement, as amended to date,
     be and hereby is further amended to delete the definition of "Preferred
     Shares" therein and replace it with the following:

          "Preferred Shares" shall mean shares of the Company's Series A
          Convertible Preferred Stock, par value $.01, per share Series B
          Convertible Preferred Stock, par value $.01 per share and Series C
          Convertible Preferred Stock, par value $.01 per share.

2.   Capitalized terms used but not otherwise defined herein shall have the
     meanings ascribed to them in the Registration Rights Agreement.

3.   In all other respects, the Registration Rights Agreement is hereby
     ratified, confirmed and approved, and all terms thereof shall remain in
     full force and effect.
<PAGE>

4.   This Amendment No. 2 may be executed in counterparts, each of which shall
     constitute an original, but all of which, when taken together, shall
     constitute but one agreement.

                      [Signature Pages Follow Immediately]

                                      -2-<PAGE>

                                                                    EXHIBIT 4.11

                                AMENDMENT NO.3

                                      TO

                         REGISTRATION RIGHTS AGREEMENT

     AMENDMENT NO. 3, dated as of December 8, 1998 by and among Adolor
Corporation, a Delaware corporation (the "Company"), certain holders of the
Company's outstanding securities (collectively, the "Existing Investors") and
those purchasers listed in Schedule I to the Series E Convertible Preferred
Stock Purchase Agreement (the "Purchase Agreement") dated the date hereof
(collectively, including such purchasers who participate in any Additional
Closing (as defined in the Purchase Agreement) and who execute a counterpart to
this Agreement, the "Purchasers").

     WHEREAS, the Company and the Existing Investors are parties to that
Registration Rights Agreement (the "Registration Rights Agreement") by and among
the Company and the parties named therein dated as of the 7th day of November
1994, as amended by Amendment No. 1 to Registration Rights Agreement dated as of
February 27, 1996 and Amendment No. 2 to Registration Rights Agreement dated as
of May 1, 1997; and

     WHEREAS, the Purchasers are purchasing from the Company and the Company is
issuing and selling to the Purchasers up to 13,333,333 shares (the "Series E
Shares") of Series E Convertible Preferred Stock, par value $01, ("Series E
Stock") of the Company at the aggregate purchase price of up to $10,000,000
pursuant to the Purchase Agreement, and

     WHEREAS, it is a condition to the sale of the Series (Pounds) Shares that
the Registration Rights Agreement be amended to grant the Purchasers certain
rights thereunder, and the parties hereto desire to amend the Registration
Rights Agreement as set forth below;

     NOW, THEREFORE in consideration of the foregoing and the promises and
covenants contained herein, the parties hereby agree as follows:

1.   That Section 1 of the Registration Rights Agreement, as amended to date, be
     and hereby is further amended to delete the definition of "Preferred
     Shares" therein and replace it with the following:

          "Preferred Shares" shall mean shares of the Company's Series A
          Convertible Preferred Stock, par value $.01 per share, Series B
          Convertible Preferred Stock, par value $.01 per share, Series C
          Convertible Preferred Stock, par value $01 per share and Series E
          Convertible Preferred Stock, par value $01 per share.

2.   That Section 3 of the Registration Rights Agreement, as amended to date, be
     and hereby is further amended by inserting the phrase "or to one or more
     members of the transferor (in the case of a transferor that is a limited
     liability company)" after the phrase "(in the case of a transferor that is
     a corporation)" on line 11 of said section.
<PAGE>

3.   That Section 13(a) of the Registration Rights Agreement, as amended to
     date, be and hereby is further amended by inserting the words", member"
     after the word "shareholder" on line 11 of said section.

4.   Capitalized terms used but not otherwise defined herein shall have the
     meanings ascribed to them in the Registration Rights Agreement.

5.   In all other respects, the Registration Rights Agreement is hereby
     ratified, confirmed and approved, and all terms thereof shall remain in
     full force and effect.

6.   This Amendment No. 3 may be executed in counterparts, each of which shall
     constitute an original, but all of which, when taken together, shall
     constitute but one agreement.

                     [Signature Pages Follow Immediately]

                                      -2-<PAGE>

                                                                    EXHIBIT 4.12

                                AMENDMENT NO.4
                                      TO
                         REGISTRATION RIGHTS AGREEMENT

     AMENDMENT NO. 4, dated as of August 1999 by and among Adolor Corporation, a
Delaware corporation (the "Company"), certain holders of the Company's
outstanding securities (collectively, the "Existing Investors") and S. R. One,
Limited (the "Purchaser").

     WHEREAS, the Company and the Existing Investors are parties to that
Registration Rights Agreement (the "Registration Rights Agreement") by and among
the Company and the parties named therein dated as of the 7th day of November
1994, as amended by Amendment No. 1 to Registration Rights Agreement dated as of
February 27, 1996, Amendment No. 2 to Registration Rights Agreement dated as of
May 1, 1997 and Amendment No. 3 to Registration Rights Agreement dated as of
December 8, 1998; and

     WHEREAS, the Purchaser is purchasing from the Company and the Company is
issuing and selling to the Purchaser 2,500,000 shares (the "Series F Shares") of
Series F Convertible Preferred Stock, par value $.01, ("Series F Stock") of the
Company at the aggregate purchase price of $2,500,000 pursuant to the Series F
Convertible Preferred Stock Purchase Agreement dated the date hereof between the
Company and Purchaser (the "Purchase Agreement:); and

     WHEREAS, it is a condition to the sale of the Series F Shares that the
Registration Rights Agreement be amended to grant the Purchaser certain rights
thereunder, and the parties hereto desire to amend the Registration Rights
Agreement as set forth below

     NOW, THEREFORE in consideration of the foregoing and the promises and
covenants contained herein, the parties hereby agree as follows:

1.   That Section 1 of the Registration Rights Agreement, as amended to date, be
     and hereby is further amended to delete the definition of "Preferred
     Shares" therein and replace it with the following:

       "Preferred Shares" shall mean shares of the Company's Series A
       Convertible Preferred Stock, par value $01 per share, Series B
       Convertible Preferred Stock, par value $01 per share, Series C
       Convertible Preferred Stock, par value $01 per share, Series E
       Convertible Preferred Stock, par value $01 per share and Series F
       Convertible Preferred Stock, par value $01 per share.

2.   Capitalized terms used but not otherwise defined herein shall have the
     meanings ascribed to them in the Registration Rights Agreement.

3.   In all other respects, the Registration Rights Agreement is hereby
     ratified, confirmed and approved, and all terms thereof shall remain in
     full force and effect.
<PAGE>

4.   This Amendment No. 4 may be executed in counterparts, each of which shall
     constitute an original, but all of which, when taken together, shall
     constitute but one agreement.

                     [Signature Pages Follow Immediately]

                                      -2-

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